A series of lipid mediators named eicosanoids, such as prostaglandins and leukotrienes, can be generically synthesized by the arachidonic acid cascade starting from arachidonic acid which is cleaved by various stimuli from membranous phospholipids. In particular, prostanoids are a type of arachidonic acid metabolites synthesized with prostaglandin H2, as an intermediate generated by cyclooxygenase in the arachidonic acid. It is known that prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2, and thromboxane A2, are also synthesized by such a biosynthetic pathway.
Prostanoids act as locally chemical transmitters like active hormones, and are generally synthesized in response to stimuli such as local tissue damage, hormones, bacterial peptides, antigens, and inflammatory mediators such as cytokines. These prostanoids manifest various effects in different tissues by binding to specific receptors on cell surfaces. In addition to regulating gastric acid secretion and blood flow, they are known to have considerable influence on inflammatory responses and immune system in the body.
Synthases that generate prostaglandin D2 are referred to as prostaglandin D synthases. It is known that two different types, hematopoietic and lipocalin-type synthase are existed.
Human hematopoietic synthases are distributed throughout the placenta, lung, fetus liver, lymphonodus, brain, heart, thymus, bone marrow, and spleen. Moreover, at the cellular level, they are reported to be expressed in microneuroglia in the brain, megakaryocytes and Langerhans cells in the skin; Kupffer cells in the liver; macrophages; and many antigen-presenting cells, such as dendritic cells, mast cells, and Th2 cells.
On the other hand, lipocalin-type synthases are distributed mainly in the central nervous system of the brain and spinal cord, the heart, the testis epithelium, and testis. It is known that not only does the prostaglandin D2 produced by lipocalin-type synthase act as a humoral regulator of sleep, and mediator of cranial nerve system control via the arachnoid membrane, nociception control as typified by allodynia, and spermatogenesis control, but also that lipocalin-type enzymes themselves have a function as transporter proteins of lipophilic low-molecular-weight compounds.
Two types of specific receptors of prostaglandin D2, DP1 and DP2 (also referred to as CRTH2), are known. It is reported that DP1 is expressed in tissues such as bone marrow, brain, retina and digestive organs, respiratory epithelial cells, vascular smooth muscle, platelets and cells such as basophils, while DP2 is expressed in tissues such as bone marrow, brain, thymus and heart, Th2 cells, and eosinophils, basophils and monocytes. The prostaglandin D2 mainly produced locally by hematopoietic synthases due to various stimuli, that binds with these receptors, has various actions such as inhibition of platelet aggregation, vasodilation, enhancement of vascular permeability, increased mucus production, airway smooth muscle contraction, and mobilization and activation of antigen-presenting cells, Th2 cells, and eosinophils. In particular, it is thought to participate in the onset and exacerbation of allergic diseases and inflammatory diseases.
In allergic diseases, such as bronchial asthma and allergic rhinitis, mast cells are activated by the binding of antigens with immunogloblin E, thereafter various inflammatory mediators are produced by the activation of an arachidonic acid cascade, which is thought to play an important role in elucidation of allergic reactions. Among these, prostaglandin D2 is the inflammatory mediator produced in the largest amounts, and it is detected at high concentration in an asthmatic's bronchoalveolar fluid (Non-patent documents 1 and 2). Further, it was reported that bronchoconstriction was simultaneously induced by prostaglandin D2 inhalation in asthmatic patients but not healthy subjects (Non-patent document 3). Moreover, from the facts that hematopoietic synthases are highly expressed in mast cells or inflammatory cells at nasal mucosa in allergic rhinitis, or nasal polyps in chronic sinusitis, DP1 and DP2 are also expressed in the infiltrated eosinophils, and DP2 is expressed in T cells (Non-patent document 4), and that in atopic dermatitis the proportion of DP2 positive skin lymphocyte homing antigen-positive cells (CLA) is high depending on the severity of symptoms (Non-patent document 5), it is thought that prostaglandin D2 produced by hematopoietic enzyme plays an important role in the onset and exacerbation of allergic diseases (Non-patent documents 6-8).
Recently, it has been reported that in prostaglandin D synthase transgenic mice, allergic responses were promoted (Non-patent document 9), whereas prostaglandin D2 receptor-knockout mice did not show allergic responses (Non-patent document 10). It was also reported that in hematopoietic synthase-deficient mice, the expansion of myonecrosis or traumatic cerebral damage is also minor.
Therefore, the prostaglandin D2 produced by these two types of enzymes, hematopoietic synthases and lipocalin-type synthases, participates in the onset and exacerbation of various diseases including allergy, and in the regulatory mechanisms of the body, so pharmaceutical preparations that can ameliorate excess production are considered to be very effective in the treatment of various diseases.
For example, as a hematopoietic synthase inhibitor, HQL-79 (4-benzhydryloxy-1-((3-(1H-tetrazol-5-yl)-propyl))piperidine) has been reported (Non-patent documents 11 and 12). Although HQL-79 is a compound having histamine H1 receptor antagonistic activity, is reported to inhibit airway inflammation such as suppression of eosinophil infiltration into the airway and the delayed asthmatic response in experimental asthmatic models, it cannot be said to have sufficient activity. Another prostaglandin D synthase inhibitor has been disclosed (Patent documents 8 and 9), and its enzyme inhibitory activity exceeds that of HQL-79, but it also does not have sufficient activity.
Anti-allergic agents currently used to prevent or treat allergic disorders include antihistamines, chemical mediator release inhibitors, leukotriene receptor antagonists, thromboxane-A2 synthesis inhibitors and receptor antagonists, Th2 cytokine inhibitors, and immunosuppressants (Non-patent document 13). However, these anti-allergic drugs cannot be said to have sufficient medicinal action, and since some of them have side-effects on the central nervous system, such as sleepiness and drowsiness; or cause digestive symptoms such as diarrhea; or cause immunosuppression; they have problematic issues and not easy to use. Moreover, although steroids are often employed for the treatment not only for allergic diseases but also for many inflammatory diseases due to their powerful anti-inflammatory action, they may lead to a higher susceptibility to infection, have an adverse effect on bone, interfere with growth, and also cause a rebound phenomenon after their use is discontinued, so they also are not easy to use.
On the other hand, it may be expected that a inhibitor of prostaglandin D synthase would be a useful drug in the prevention and/or treatment of allergic or inflammatory diseases in which prostaglandin D2 produced by hematopoietic synthase or their metabolites are involved.
Conventionally, benzimidazole compounds have been widely studied as useful pharmacological agents.
For example, in Patent document 1 (International Publication WO No. 2004017963), a wide range of benzimidazole compounds including 5-phenoxy benzimidazole) are described as blood coagulation factor Xa inhibitors.
In Patent document 2 (JP-A 2004-067629), a 5-phenoxybenzimidazole compound and 5-benzoylbenzimidazole compound are described as mitochondrion functional activators.
In Patent document 3 (International Publication WO No. 2003035065), a wide range of benzimidazole compounds including a 5-phenoxybenzimidazole compound and 5-benzoylbenzimidazole compound are described as protein kinase inhibitors.
In Patent document 4 (Patent No. 2001-515482), a 5-phenoxybenzimidazole compound and 5-benzoylbenzimidazole compound are described as FBP-ase inhibitors.
In Patent document 5 (International Publication WO No. 2002076454), a 5-phenoxybenzimidazole compound and 5-benzoylbenzimidazole compound are described as pharmaceutical applications of an antitumor agent.
In Patent document 6 (JP-A 2000-026430), a 5-phenoxybenzimidazole compound is described wherein pyridyl, furyl, and thienyl are substituents at position 2 of the benzimidazole.
In Patent document 7 (International Publication WO No. 9965886), a 5-benzoylbenzimidazole compound is described as an insect and mite repellent, wherein a thiazolyl group is disclosed as the heterocyclic ring of the substituent at position 2 of the benzimidazole.    Patent document 1: International Publication No. WO 2004017963    Patent document 2: Japanese Unexamined Patent Publication No. 2004-067629    Patent document 3: International Publication No. WO 2003035065    Patent document 4: Japanese Unexamined Patent Publication No. 2001-515482    Patent document 5: International Publication No. WO 2002076454    Patent document 6: Japanese Unexamined Patent Publication No. 2000-026430    Patent document 7: International Publication No. WO 9965886    Patent document 8: Japanese Unexamined Patent Publication No. 2004-2248    Patent document 9: Japanese Unexamined Patent Publication No. 2004-51600    Non-patent document 1: J. Immumol., 129, 1627-1631 (1982)    Non-patent document 2: N. Eng. J. Med., 315, 800-804 (1986)    Non-patent document 3: N. Eng., J. Med., 311, 209-213 (1984)    Non-patent document 4: Prostaglandins & Other Lipid, Med. 73, 87-101 (2004)    Non-patent document 5: J. Invest. Dermatol. 119, 609-616 (2002)    Non-patent document 6: J. Immunol., 143, 2982-2989 (1989)    Non-patent document 7: J. Biol. Chem., 265, 371-375 (1990)    Non-patent document 8: J. Biol. Chem., 270, 3239-3246 (1995)    Non-patent document 9: J. Immunol., 168, 443-449 (2002)    Non-patent document 10: Science, 287, 2013-2017 (2000)    Non-patent document 11: Jpn. J. Pharmacol., 78, 1-10 (1998)    Non-patent document 12: Jpn. J. Pharmacol., 78, 11-22 (1998)    Non-patent document 13: “Rinsho to Kenkyu (Japanese Journal of Clinical and Experimental Medicine)”, vol. 79, No. 2, pp. 30-33 (February, 2002)